The pursuit of serine protease inhibitors as anticoagulants and anti-hepatitis C virus drugs continues to be an active area of research. Compounds such as P1-P3 macrocyclic peptides and linear peptides have been registered as potent hepatitis C virus protease inhibitors and compounds such as phenylglycinamide derivatives, substituted biaryls, tetrahydroquinoline derivatives, arylpropionamides, arylacrylamides, arylpropynamides, arylmethylurea analogs and peptides as factor XIa inhibitors. Given the recent US FDA approval of telaprevir and boceprevir for the treatment of hepatitis C virus, the development of new serine protease inhibitors is likely to be one of the hottest areas in the pharmaceutical industry. This review covers the patent literature on serine protease inhibitors during the period between 2009 and 2010.